Current therapies for human stroke have limited efficacy. Recent studies indicate that there are protective mechanisms residing within the brain that can be activated using preconditioning stimuli. Identification of these mechanisms may provide new therapeutic targets for stroke in humans. The central hypothesis of this proposal is that preconditioning upregulates inhibitors of inflammation that protect the brain against ischemia. Enhancing the expression of inflammatory inhibitors after stroke is a novel strategy to attenuate ischemic damage. The central hypothesis will be tested in four specific aims. First, the timecourse of and regional expression of selected inhibitorsof inflammation will be measured after preconditioning. Second, the causative relationship between these inhibitors and neuroprotection will be assessed by determining whether attenuation of their expression abrogates the induction of tolerance to ischemia. Third, we will determine whether agents that specifically activate Toll-like receptors upregulate inhibitors of inflammation and induce tolerance to ischemia. Finally, we will determine whether neurotrophic factors, known to be upregulated by preconditioning, themselves increase the expression of inhibitors of inflammation and whether antagonism of this expression attenuates the protective effects of the neurotrophins against ischemia. These studies will test whether upregulation of inhibitors of inflammation is a major mechanism contributing to ischemic tolerance. Enhancement of endogenous pathways that suppress inflammation is an innovative and promising strategy for the treatment of stroke in humans.